EP2797910B1 - Esters de quinuclidine et d'acide 1-azahétérocyclylacétique utilisés comme agents antimuscariniques, procédé pour leur préparation et compositions médicinales correspondantes - Google Patents

Esters de quinuclidine et d'acide 1-azahétérocyclylacétique utilisés comme agents antimuscariniques, procédé pour leur préparation et compositions médicinales correspondantes Download PDF

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EP2797910B1
EP2797910B1 EP12818780.4A EP12818780A EP2797910B1 EP 2797910 B1 EP2797910 B1 EP 2797910B1 EP 12818780 A EP12818780 A EP 12818780A EP 2797910 B1 EP2797910 B1 EP 2797910B1
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mmol
group
alkyl
piperidin
preparation
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EP2797910A1 (fr
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Gabriele Amari
Cristina PESENTI
Stefano Bossolo
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Chiesi Farmaceutici SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to quinuclidine ester of 1-azaheterocyclylacetic acid analogues acting as muscarinic receptor antagonists, a process for their preparation, a composition comprising them and the therapeutic use thereof.
  • Quaternary ammonium salts acting as muscarinic (M) receptor antagonist drugs are currently used in therapy to induce bronchodilation for the treatment of respiratory diseases.
  • M receptor antagonists are represented by ipratropium bromide and tiotropium bromide.
  • Quinuclidine carbamate derivatives and their use as M3 antagonists are for instance disclosed in WO 02/051841 , WO 03/053966 and WO 2008/012290 .
  • WO 2010/015324 describes carbonate derivatives and their use as M3 antagonists.
  • 1-ethyl-3-piperidinyl ester of optionally substituted alpha-phenyl-1-piperidine- / 1-pyrrolidine- / 4-morpholine- acetic acid have been described for their spasmolytic activity with respect to acetylcholine in US 2952685 and in Bull Soc Chim France 355-359, 1958 .
  • Quaternary ammonium salts of quinuclidine esters of alfa-phenyl-alfa-methyl-1-piperidine-acetic acid and analogues have been described in WO 2008/075005 , WO 2009/153536 and Bioorg Med Chem Lett (2011 ),doi:10.1016/j.bmcl.2011.10.002.
  • Said compounds having a methyl group in place of the hydroxyl group of the well known M3 antagonists of the prior art would have higher probability to bind to plasma proteins.
  • M3 receptor antagonists it is however highly desirable to provide M3 receptor antagonists to be administered by inhalation, able to act locally, while having high potency and long duration of action. Said drugs, once adsorbed, should be degraded to inactive compounds which are deprived of any systemic side effects typical of muscarinic antagonists.
  • the present invention provides quinuclidine ester of 1-azaheterocyclylacetic acid analogues, of general formula (I), as selective M3 receptor antagonists capable to be administered by inhalation and to act locally.
  • a compound according to the invention is able to produce a persistent bronchodilating effect in the lung but is consistently and rapidly transformed into inactive metabolites after passing into human plasma. This behaviour gives great advantages in terms of safety.
  • the present invention is also directed to a compound of general formula (II):
  • a , R1, m and n are as described above and a pharmaceutical acceptable salt thereof.
  • the invention also concerns a process for the preparation of a compound of formula (I) as reported in Scheme 1 by:
  • the invention also provides pharmaceutical compositions of compounds of general formula (I) or of general formula (II) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention also provides compounds of general formula (I) or (II) for use as a medicament.
  • the invention provides the use of compounds of formula (I) or of general formula (II) for the manufacture of a medicament for the prevention and/or treatment of broncho-obstructive or inflammatory diseases, preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
  • broncho-obstructive or inflammatory diseases preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • broncho-obstructive or inflammatory diseases preferably asthma or chronic bronchitis or chronic obstructive pulmonary disease (COPD)
  • COPD chronic obstructive pulmonary disease
  • the invention also provides pharmaceutical preparations of compounds of general formula (I) or of general formula (II) suitable for administration by inhalation, such as inhalable powders, propellant-driven pressurised metered dose aerosol inhalers or propellant-free inhalable formulations.
  • the invention also refers to a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer comprising the compounds of general formula (I) or (II).
  • the invention also refers to a kit comprising the pharmaceutical compositions of compounds of general formula (I) or (II) alone or in combination with or in admixture with one or more pharmaceutically acceptable carriers and/or excipients and a device which may be a single- or multi-dose dry powder inhaler, a metered dose inhaler and a soft mist nebulizer comprising the compounds of general formula (I) or (II).
  • halogen includes fluorine, chlorine, bromine and iodine atoms.
  • (C 1 -C 10 )alkyl refers to straight or branched chain alkyl groups wherein the number of carbon atoms is from 1 to 10. Examples of said groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like.
  • (C 2 -C 6 )alkenyl refers to straight or branched carbon chains with one or more double bonds. Examples of said groups are ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • (C 1 -C 10 )alkoxyl refers to the above alkyl-oxy (e.g. alkoxy) groups. Examples of said groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy and the like.
  • (C 1 -C 10 )alkanoyl refers to a carbonyl residue substituted by a hydrogen atom or by a straight or branched alkyl group from 1 to 9 carbon atoms. Examples of said groups are formyl, acetyl, propanoyl, butanoyl, isobutanoyl and pivaloyl.
  • (C 1 -C 10 )alkylsulfanyl refers, respectively, to alkylS-, alkyl-SO- or alkyl-SO 2 - groups.
  • (C 3 -C 8 )cycloalkyl refers to cyclic non-aromatic hydrocarbon groups with 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • (C 5 -C 10 )heterocycloalkyl refers to cyclic non-aromatic systems which have 5 to 10 ring atoms, in which at least one ring atom is a heteroatom (e.g. N, NH, S or O).
  • aryl refers to mono or bi- or tricyclic ring systems which have 6 to 20 ring atoms, preferably 6 to 15 and wherein at least one ring is aromatic.
  • aryl(C 1 -C 6 )alkyl refers to (C 1 -C 6 )alkyl groups further substituted by aryl or heteroaryl rings.
  • aryloxy refers to the above aryl-oxy group.
  • An example may be phenyloxy.
  • heteroaryl refers to mono, bi- or tricyclic ring systems which have 5 to 20 ring atoms, preferably 5 to 15, in which at least one ring is aromatic and in which at least one ring atom is a heteroatom or heteroaromatic group (e.g. N, NH, S or O).
  • Suitable aryl or heteroaryl monocyclic systems include for instance thienyl (thiophenyl), phenyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, pyridinyl, imidazolidinyl and furanyl residues and the like.
  • Suitable aryl or heteroaryl bicyclic systems include benzodioxole, naphthalene, biphenylene, purine, pteridine, benzotriazole, quinoline, isoquinoline, indole, isoindole, benzothiophene, dihydrobenzo dioxin, dihydrobenzo dioxepin and benzo oxazin residues and the like.
  • physiologically acceptable anions X - include those selected from chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulfonate.
  • additional physiological and/or pharmaceutically acceptable anions may be present to form an acid addition salt with an inorganic or organic acid.
  • acidic groups such as COOH groups
  • corresponding physiological cation salts may be present as well, for instance including alkali or earth-alkali metal ion or an ammonium ion.
  • Suitable inorganic acid to form an acid addition salt of a compound of formula (I) or (II) are selected from hydrohalogen acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid, but also from nitric acid, sulfuric acid and phosphoric acid.
  • Suitable organic acids to form an acid addition salt of a compound of formula (I) or (II) are selected from: aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid; aliphatic hydroxy acids such as lactic, citric, tartaric and malic acids; dicarboxylic acids such as maleic or succinic acid; aromatic carboxylic acids such as benzoic acid; aromatic hydroxy acids and sulfonic acids.
  • a first preferred group of compounds of general formula (I) or (II) is that wherein A is selected from O, S, N(R 3 ) or C(R 3 )R 4 , R1 is selected from the group consisting of aryl, aryl(C 1 -C 6 )alkyl and heteroaryl, optionally substituted by one or more substituents selected from halogen atoms, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxyl, aryloxy and heteroaryl; and R2 , R3 and R4 are as defined above.
  • A is C(R 3 )R 4
  • R1 is selected from the group consisting of aryl and heteroaryl, optionally substituted by one or more substituents selected from halogen atoms, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxyl, aryloxy and heteroaryl
  • m and n are both 2
  • R2 is a group of formula (Y) wherein p is 0, 1 and 3, P is CO, q is 0, W is selected from the group consisting of (C 1 -C 10 )alkyl, aryl, heteroaryl, optionally substituted by one or more substituents selected from the group consisting of halogen atoms, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxyl, OH and (C 1 -C 10 )alkanoyl.
  • W is selected from the group consisting of phenyl, benzothioxol, thiophenyl and thiazolyl, optionally substituted by one or more halogen atoms, OH, methyl and acetyl.
  • the active compounds of general formula (I) and (II) show at least two chiral centers, which are respectively represented by the quinuclidine carbon atom bearing the oxygen ester group and the carbon atom bearing R1 group.
  • These compounds of general formula (I) and (II) can be obtained in pure S-R, R-R, R-S, S-S configurations or as mixtures of diastereoisomers.
  • the invention also includes any of the optical stereoisomers, diastereoisomers and mixtures thereof, in any proportion.
  • the present invention provides the compounds reported below: Compound Chemical name C3 (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate C4 (3R)-1-(2-oxo-2-phenylethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azonia bicyclo[2.2.2]octane bromide C5 (3R)-1-(2-oxo-2-(thiophen-2-yl)ethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azonia-bicyclo[2.2.2]octane trifluoroacetate trifluoroacetate anion C6 (3R)-1-(2-(4-chlorophenyl)-2-oxoethyl)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-azoniabicyclo
  • Compounds of general formula (IX) may be prepared according to standard procedures extensively reported in literature (for example following the procedure reported by Kiskinen et al. in Tetrahedron, 1983, 39/9, 1627 ; Haurena et al. in J.O.C., 2010, 75/8, 264 ; Najer, Bulletin de la Societe Chimique de France, 1958, 1189 ; Duan et al. Bioorganic and Medicinal Chemistry Letters, 2009, 19/6, 1610 ). Most preferably, the compounds of general formula (IX) may be prepared according to three different routes: A, B and C.
  • LG is a suitable leaving group (an halide such as a bromide or a sulfonic ester group such as a mesylate)
  • This alkylation can be carried out following one of the standard procedures broadly reported in literature (for instance, Melloni et al., European Journal of Medicinal Chemistry, 1984, 19/3, 235 ; Duran et al., Journal of Medicinal Chemistry, 1965, 8, 598 ; Venkatesan, A.M. et al., Journal of Medicinal Chemistry, 2004, 47/25, 6255 ; Wlasislaw, B. et al. Synthesis, 1997, 4, 420 ).
  • the alkylation reaction is promoted by the presence of a base, for instance an amine selected from the group consisting of triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine or an inorganic base such as potassium carbonate or sodium hydride.
  • a base for instance an amine selected from the group consisting of triethylamine, diisopropylethylamine, pyridine and 4-dimethylaminopyridine or an inorganic base such as potassium carbonate or sodium hydride.
  • the reaction is generally performed in a suitable solvent (e.g. acetonitrile, THF, DMF) in a temperature range from about 0°C to about 130°C over a period of about 1 hour up to about 74 hours.
  • the reaction may be conducted under conventional heating (using an oil bath) or under microwave heating.
  • the reaction may be carried out in an open vessel or in a sealed tube.
  • Reagents of general formula (IV) are commercially available or may be conveniently prepared according to standard procedures extensively reported in literature.
  • compounds of general formula (IV) in which LG is a halogen such as a bromine may be prepared by halogenation of the opportunely substituted phenyl acetic ester (for example following the procedure reported by Epstein, J.W. in J.Med.Chem., 1981, 24/5, 481 ).
  • compounds of general formula (IV) may be prepared starting from the appropriately substituted mandelic derivative (IV), using known procedures (a survey of the suitable reactions is given by Larock, L.C., Comprehensive Organic Transformation, Second edition (1999), John Wiley & Son Inc, pg 689-700 ).
  • the mandelic derivative of general formula (IV) can be directly coupled with reagent of general formula (III) by means of Mitsunobu reaction ( Kumara Swamy, K.C. et al. Chem. Rev. 2009, 109, 2551 ; Powell, N.A. et al. Bioorganic and Medicinal Chemistry 2007, 15/17, 5912 ).
  • the reaction typically was conducted in the presence of a phosphine (e.g. triphenylphosphine) and azodicarboxylate (e.g.
  • diisopropyl azodicarboxylate or diethyl azodicarboxylate in a suitable solvent (such as DCM and THF) and in a temperature range from -10°C to 110°C over a period of 1 hour up to 74 hours.
  • compounds of general formula (IX) might be prepared by means of a Petasis-Mannich reaction following one of the different procedures reported in literature (e.g.: Petasis N. A., Akritopoulou I., Tetrahedron Lett. 1993, 34, 583 ; Follmann, M., Synlett, 2005, 6, 1009 ; Kausik K.N., Tetrahedron Letters, 2005, 46, 2025 ).
  • a suitable solvent e.g. dichloromethane, acetonitrile
  • This reaction is usually performed in a temperature range from about 0°C to about 110°C over a period of about 1 hour to about 74 hours.
  • the reaction may be conducted under conventional heating (using an oil bath) or under microwave heating.
  • the reaction may be carried out in an open vessel or in a sealed tube.
  • Route C Compounds of general formula (IX) might be prepared starting from the suitable aminoacid derivatives of general formula (VIII). These reagents can be converted into compounds of general formula (IX) using known protocols (e.g. Benasutti et al., Tetrahedron Asymmetry, 2006, 17/5, 842 ; Benson et al., J.O.C., 1988, 53/22, 5335 ; Cuevas et al., Synlett, 2007, 1, 119 ; Juarez et al., Tetrahedron Asymmetry, 1997, 8/2, 203 ).
  • known protocols e.g. Benasutti et al., Tetrahedron Asymmetry, 2006, 17/5, 842 ; Benson et al., J.O.C., 1988, 53/22, 5335 ; Cuevas et al., Synlett, 2007, 1, 119 ; Juarez et al., Tetrahedron Asymmetry, 1997, 8/2, 203
  • K may be an alkoxy group, an hydroxyl group or an halogen such as chlorine (a survey of the suitable reactions is given by Carey, F.A. and Sundeberg, R.J. Advanced Organic Chemistry, Third Edition (1990), Plenum Press, New York and London, pg 145 ).
  • K an alkoxy group
  • X quinuclidin-3-ol salts
  • J Na, Li or K.
  • a solution of the esters (IX) and the opportune salts of quinuclidin-3-ol previously performed or generated in situ
  • a suitable solvent e.g. toluene, DMF or NMP
  • hydrolysis of ester moiety in (IX) may be performed treating these compounds with a suitable aqueous base selected from the group consisting of sodium, lithium and potassium hydroxide in the opportune solvents (e.g. tetrahydrofuran, dioxane, water etc).
  • a suitable aqueous base selected from the group consisting of sodium, lithium and potassium hydroxide in the opportune solvents (e.g. tetrahydrofuran, dioxane, water etc).
  • RT room temperature
  • the resulting carboxylic acid could be coupled to quinuclidin-3-ol according to several protocols.
  • a commercially available condensing agent such as a carbodiimide (e.g. 1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDC) and the like) for example in the presence of N-hydroxybenzotriazole (HOBt) followed by reaction of the activated intermediate with alcohol (X), results in the formation of compounds (II).
  • a commercially available condensing agent such as a carbodiimide (e.g. 1-(3-dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (EDC) and the like) for example in the presence of N-hydroxybenzotriazole (HOBt) followed by reaction of the activated intermediate with alcohol (X), results in the formation of compounds (II
  • An organic base such as triethylamine may be also present in the reaction mixture.
  • the activated intermediate may be either isolated, or pre-formed or generated in situ.
  • Suitable solvents for the coupling include, but are not limited to, halocarbon solvents (e.g. dichloromethane), tetrahydrofuran, dioxane and acetonitrile.
  • the reaction proceeds at temperature range from 0°C up to 170°C, for a time in the range of about 1 hour up to 72 hours.
  • the reaction may be carried out under conventional heating (using an oil bath) or under microwave irradiation.
  • the reaction may be conducted either in an open vessel or in a sealed tube.
  • the reaction may be promoted by a base such as triethylamine, pyridine and 4-dimethylaminopyridine, in a suitable solvent (e.g. dichloromethane). This reaction is performed in a temperature range from 0°C to 130°C over a period of 1 hour up to 74 hours.
  • the reaction may be conducted under conventional heating (using an oil bath) or under microwave heating.
  • the reaction may be carried out in an open vessel or in a sealed tube.
  • DMF dimethylformamide
  • activating agents such as bromotripyrrolidinophosphonium hexafluorophosphate (PyBrOP) or carbonylimidazole
  • suitable aprotic solvent e.g. dichloromethane, tetrahydrofuran
  • the reaction may also require the use of an organic base such as diisopropylethylamine and usually proceeds at about RT.
  • acids (IX) and alcohol (X) are reacted in presence of a phosphine (e.g. triphenylphosphine) and an azadicarboxylate ester (e.g. diethyl azodicarboxylate or diisopropyl azodicarboxylate) in an aprotic solvent such as tetrahydrofuran.
  • a phosphine e.g. triphenylphosphine
  • an azadicarboxylate ester e.g. diethyl azodicarboxylate or diisopropyl azodicarboxylate
  • aprotic solvent such as tetrahydrofuran.
  • Compound of general formula (II), in which R1, A, m and n are defined hereinbefore, can be achieved either as single diastereoisomer or as a mixture of diastereoisomers.
  • the quinuclidin-3-ol can feature either a R or a S configuration. If R-enantiomer is used, compound (II) can be obtained in S-R configuration, in R-R configuration or as a mixture of diastereoisomers (R-R and S-R configuration).
  • separation of diastereoisomers may be obtained using a column filled with a chiral stationary phase, for example Chiralpack AY or Chiralcel OD or Chiralcel OZ, and eluting, for example, with acetonitrile and/or with mixtures of acetonitrile and an alcohol.
  • a chiral stationary phase for example Chiralpack AY or Chiralcel OD or Chiralcel OZ
  • the separation of diastereoisomers may be most conveniently achieved by crystallization from an opportune solvent (e.g. ethyl ether), as a free base or after the formation of a suitable salt (e.g. (+)-tartaric acid)).
  • alkylation of compounds of general formula (II) by alkylating agents of general formula (XI) X-R2 (XI) in which X is a suitable leaving group selected from the group consisting of halide (i.e. bromine, iodine, chlorine) and sulfonate ester (i.e. tosylate, triflates, mesylate) provides compounds of general formula (I).
  • reaction may be performed neat or in a suitable solvent selected from the group consisting of acetonitrile, DMF, DMSO and tetrahydrofuran.
  • the reaction typically proceeds at temperature range from 0°C up to 170°C, for a time in the range of few minutes up to 72 hours.
  • the reaction may be carried out under conventional heating (using an oil bath) or under microwave irradiation.
  • the reaction may be conducted either in an open vessel or in a sealed tube.
  • a compound of general formula (I) and (II) in Scheme 1 can be either considered as final product or as an intermediate to prepare other compounds of general formula (I) and (II).
  • a moiety of R1, R2 or A group in general formula (I) and (II) could undergo reactions of oxidation, reduction or cleavage (e.g to remove a protecting group) to afford other final compounds of general formula (I) and (II).
  • the present invention also provides a pharmaceutical composition of a compound of general formula (I) or (II) in admixture with one or more pharmaceutically acceptable carrier or excipient, for example those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A .
  • Administration of the compounds of the present invention may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion), by inhalation, rectally, vaginally, topically, locally, transdermally, and by ocular administration.
  • solid oral dosage forms can be used for administering compounds of the invention including such solid forms as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the compounds of the present invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and excipients known in the art, including but not limited to suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • Time release capsules, tablets and gels are also advantageous in administering the compounds of the present invention.
  • liquid oral dosage forms can also be used for administering compounds of the invention, including aqueous and nonaqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • dosage forms can also contain suitable inert diluents known in the art such as water and suitable excipients known in the art such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the compounds of the present invention may be injected, for example, intravenously, in the form of an isotonic sterile solution. Other preparations are also possible.
  • Suppositories for rectal administration of the compounds of the present invention can be prepared by mixing the compound with a suitable excipient such as cocoa butter, salicylates and polyethylene glycols.
  • Formulations for vaginal administration can be in the form of cream, gel, paste, foam, or spray formula containing, in addition to the active ingredient, such suitable carriers as are known in the art.
  • the pharmaceutical composition can be in the form of creams, ointments, liniments, lotions, emulsions, suspensions, gels, solutions, pastes, powders, sprays, and drops suitable for administration to the skin, eye, ear or nose. Topical administration may also involve transdermal administration via means such as transdermal patches.
  • the compounds according to the invention are preferably administered by inhalation.
  • Inhalable preparations include powders for inhalation, propellant-driven pressurised metered dose aerosol inhalers or propellant-free nebulised formulations.
  • the compound of the invention in powder form may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier generally non-toxic and chemically inert to the compound of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compound of the invention.
  • Propellant-driven pressurised metered dose aerosol inhalers contains the compound of the invention either in solution or in dispersed form in at least a propellant gas such as a hydrofluoroalkane.
  • the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compound of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers or by soft-mist nebulizers.
  • the compound of the invention may be administered as the sole active agent or in combination with one or more pharmaceutical active ingredients currently used in the treatment of obstructive, inflammatory respiratory disorders, selected from the classes of beta2-agonists, corticosteroids and anticholinergic or antimuscarinic agents.
  • the dosages of the compounds of the present invention depend upon a variety of factors including the particular disease to be treated, the severity of the symptoms, the route of administration, the frequency of the dosage interval, the particular compound utilized, the efficacy, toxicology profile, and pharmacokinetic profile of the compound.
  • the compounds of formula (I) and (II) can be administered for example, at a dosage comprised between 0.001 and 1000 mg/day, preferably between 0.1 and 500 mg/day.
  • the compounds of formula (I) and (II) are administered by inhalation route, they are preferably given at a dosage comprised between 0.001 and 500 mg/day, preferably between 0.1 and 200 mg/day.
  • the compounds of formula (I) and (II) may be administered for the prevention and/or treatment of any disease wherein M3 antagonists are active.
  • Said disease include: diseases involving inflammation such as asthma and COPD, acute rhinitis; diseases involving the gastrointestinal tract such as peptic ulcer; diseases involving the cardiovascular system such as acute myocardial infarction; diseases involving the genitourinary tract such as renal colic; anticholinesterase and mushroom poisoning; uses in anesthesia; uses in ophthalmology.
  • Neurode disorders such as Parkinsonism and motion sickness.
  • the compounds of formula (I) and (II) may be used for the prevention and/or treatment of respiratory diseases such as from mild to acute severe conditions of asthma and COPD.
  • respiratory diseases include bronchitis, bronchiolitis, bronchiectasis, acute nasopharyngitis, acute and chronic sinusitis, maxillary sinusitis, pharyngitis, tonsillitis, laryngitis, tracheitis, epiglottitis, croup, chronic disease of tonsils and adenoids, hypertrophy of tonsils and adenoids, peritonsillar abscess, rhinitis, abscess or ulcer and nose, pneumonia, viral and bacterial pneumonia, bronchopneumonia, influenza, extrinsic allergic alveolitis, coal workers' pneumoconiosis, asbestosis, pneumoconiosis, pneumonopathy, respiratory conditions due to chemical fumes, vapors and other external agents, emphysema, pleurisy, pneumothorax, abscess of lung and mediastinum, pulmonary congestion and hypostasis, postinflammatory pulmonary fibrosis, other al
  • Benzoyl chloride (1.60 ml, 13.8 mmol) was added to a suspension of 2-chloro-N'-lrydroxyacetimidamide (1.0 g, 9.21 mmol) in DCM (25 ml), stirring at room temperature. After 30 min., TEA (1.41 ml, 10.1 mmol) was added to the white suspension and the mixture was stirred for 30 additional min (UPLC-MS: complete conversion). The solution was diluted with DCM (20 ml) and water (30 ml) was added. The aqueous phase was extracted three times with DCM (15 ml x 3) and then the combined organic phases were dried (Na 2 SO 4 ) and evaporated.
  • PS-DCC (loading: 1.25 mmol/g; 0.99 g, 1.24 mmol) was suspended in dry THF (12 ml).
  • HOBT (0.19 g, 1.24 mmol)
  • 2-phenyl-2-(pyrrolidin-1-yl)acetic acid hydrochloride (0.15 g, 0.62 mmol)
  • (R)-quinuclidin-3-ol (0.24 g, 1.86 mmol) were sequentially added.
  • the mixture was shaken overnight and then PS-DCC was filtered washing with EtOAc and THF. The solution was evaporated and the residue was dissolved in EtOAc (30 ml) and washed with water (15 ml) and with a sat. NaHCO 3 (20 ml).
  • PS-DCC (loading: 1.25 mmol/g; 0.93 g, 1.16 mmol) was suspended in dry THF (11.6 ml) and HOBT (0.18 g, 1.16 mmol), 2-morpholino-2-phenylacetic acid hydrochloride (0.15 g, 0.58 mmol) and (R)-quinuclidin-3-ol (0.22 g, 1.75 mmol) were sequentially added. The mixture was shaken overnight and then PS-DCC was filtered off washing with EtOAc and THF. The solution was evaporated and the residue was dissolved in EtOAc (30 ml) and washed with water and then with a sat. NaHCO 3 .
  • PS-DCC (loading: 1.25 mmol/g; 0.73 g, 0.91 mmol) was suspended in dry THF (9 ml). HOBT (0.14 g, 0.91 mmol), 2-phenyl-2-thiomorpholinoacetic acid hydrochloride (0.12 g, 0.46 mmol) and (R)-quinuclidin-3-ol (0.17 g, 1.37 mmol) were sequentially added. The mixture was shaken overnight. PS-DCC was filtered off and washed with EtOAc and THF. The solution was evaporated and the residue was portioned between EtOAc and water. The organic phase was washed with sat.
  • CHO-K1 clone cells expressing the human M1-, M2-, M3-receptors were harvested in Ca ++ /Mg ++ free phosphate-buffered saline and collected by centrifugation at 1500 rpm for 10 min, at 4°C min. The pellets were resuspended in ice cold buffer A (15 mM Tris-HCl pH 7.4, 2 mM MgCl 2 , 0.3 mM EDTA, 1 mM EGTA).
  • Cloned cells expressing M1-, M2-, and M3- receptors were homogenized by a PBI politron (setting 5 for 15 s).
  • the crude membrane fraction was collected by two consecutive centrifugation steps at 40000 g for 20 min at 4°C, separated by a washing step in buffer A.
  • pellets obtained from the three cell lines were finally resuspended in buffer C (75 mM Tris HCl pH 7.4, 12.5mM MgCl 2 , 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose) and aliquots were stored at - 80°C.
  • M1-, M2-, and M3-receptor frozen membranes were resuspended in buffer D (50 mM Tris-HCl pH 7.4, 2.5 mM MgCl 2 , 1 mM EDTA).
  • the non selective muscarinic radioligand [3H]-N-methyl scopolamine ( Mol. Pharmacol. 45:899-907 ) was used to label the M1, M2, and M3 binding sites.
  • Binding experiments were performed in duplicate (ten point concentrations curves) in 96 well plates at radioligand concentration of 0.1-0.3 nM. The non specific binding was determined in the presence of cold N-methyl scopolamine 10 ⁇ M. Samples (final volume 0.75 mL) were incubated at RT for 120 min for M1, 60 min for M2 and 90 min for M3 binding assay.
  • the reaction was terminated by rapid filtration through GF/B Unifilter plates and two washes (0.75 mL) with cold buffer using a Packard Filtermate Harvester. Radioactivity on the filters was measured by a microplate scintillation counter TopCount NXT (Canberra Packard).
  • Ki values for the tested compounds were determined from the observed IC50 values according to known methods. A lower Ki value indicates that the tested compound has a higher binding affinity for the receptor.
  • M3 muscarinic receptors The interaction with M3 muscarinic receptors can be estimated by the results of in vitro studies which evaluated the potency of the test compounds and the offset of the inhibitory activity produced after washout of the antagonists in isolated guinea pig trachea and by the in vivo duration of action against acetylcholine-induced bronchospasm in the guinea pig.
  • a cumulative concentration-response curve to test antagonists was constructed on preparations precontracted by carbachol, until a complete inhibition of smooth muscle tone was achieved.
  • the concentration of antagonist producing a 50% reversal of carbachol-induced tonic contraction (IC 50 ) was taken as a measure of its potency in this bioassay.
  • the minimal concentration of the test compounds known to produce a maximal inhibitory effect was administered to carbachol-precontracted preparations. As soon as the tonic contraction was completely reversed, the organ bath solution was renewed and preparations were thoroughly washed with fresh Krebs solution. Carbachol (0.3 ⁇ M) was administered again (at 30 min interval between washout and next administration) during the next 4 hours.
  • the inhibitory effects of the compounds of the invention were expressed as percentage of the recovery of the contracting response to carbachol.
  • the percentage of recovery four hours after the washout was lower than 50%.
  • IC 50s The values (IC 50s ) of inhibitory M3 activity tested on C3 to C109 are comprised between 0.39 and 130 nM.
  • the bronchodilator activity of the tested compounds persisted unchanged up to 24 hours after the administration.
  • Plasma stability is calculated as percentage remaining after 1 and 5 hours by dividing the peak area at 1 or 5 hours by the area of the peak at time 0.
  • plasma stability being tested for some representative compounds of the invention result to be comprised between 10 and 70% compound remaining, indicating that the compounds of the invention are unstable in human plasma with respect to similar prior art compounds showing, after 1 and 5 h, a percent compound remaining in human plasma very closed to 100%.

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Claims (15)

  1. Ester de quinuclidine de l'acide 1-azahétérocyclylacétique de formule générale (I)
    Figure imgb0053
     dans laquelle :
    A peut être une simple liaison, une double liaison, l'atome O, S, le groupe SO, SO2, NR3, C(R3)R4, CO, C(O)N(R3), N(R3)C(O)O, SO2N(R3), N(R3)C(O), OC(O)N(R3), N(R3)SO2, C(R3)=C(R4) et C(R3)-(CH2)-C(R4) ;
    m est un nombre entier d'une valeur de 1 à 4 ;
    n a la valeur de 0 ou est un nombre entier d'une valeur de 1 à 4 ;
    R1 est sélectionné dans le groupe constitué du groupe alkyle en C1 à C10, aryle, cycloalkyle en C3 à C8, hétéroaryle, aryl(alkyle en C1 à C6) et hétéroaryl(alkyle en C1 à C6), éventuellement substitué par un ou plusieurs substituants sélectionnés dans le groupe constitué des atomes d'halogène, du groupe OH, oxo (=O), SH, NO2, CN, CON(R3)2, COOH, CO2R3, CF3, alcoxycarbonyle en C1 à C10, alkylsulfanyle en C1 à C10, alkylsulfinyle en C1 à C10, alkylsulfonyle en C1 à C10, alkyle en C1 à C10, alcoxyle en C1 à C10, aryloxy et hétéroaryle ;
    X- est un anion physiologiquement acceptable ;
    R2 est un groupe de formule (Y)

            ---(CH2)p---P---(CH2)q---W     (Y)

    dans laquelle
    p a la valeur de 0 ou est un nombre entier d'une valeur de 1 à 4 ;
    q a la valeur de 0 ou est un nombre entier d'une valeur de 1 à 4 ;
    P est absent ou est sélectionné dans le groupe constitué de O, S, SO, SO2, CO, NR3, CH=CH, N(R3)SO2, N(R3)COO, N(R3)C(O), SO2N(R3), OC(O)N(R3) et C(O)N(R3) ;
    W est sélectionné dans le groupe constitué de l'atome H, du groupe alkyle en C1 à C10, alcoxyle en C1 à C10, cycloalkyle en C3 à C8, aryle, hétéroaryle, hétérocycloalkyle en C5 à C10, éventuellement substitué par un ou plusieurs substituants sélectionnés dans le groupe constitué des atomes d'halogène, du groupe OH, oxo (=O), SH, NO2, CN, CON(R3)2, COOH, NH2, NHCOR3, CO2R3, alcoxycarbonyle en C1 à C10, alkylsulfanyle en C1 à C10, alkylsulfinyle en C1 à C10, alkylsulfonyle en C1 à C10, alkyle en C1 à C10, alcoxyle en C1 à C10, alcanoyle en C1 à C10 et aryle ;
    R3 et R4 sont indépendamment sélectionnés dans le groupe constitué de l'atome H, des atomes d'halogène, du groupe CONH2, alkyle en C1 à C10, alcynyle en C2 à C6, alcényle en C2 à C6, alcanoyle en C1 à C10, cycloalkyle en C3 à C8, hétéroaryle, et aryle éventuellement substitué par un ou plusieurs substituants sélectionnés dans le groupe constitué des atomes d'halogène, du groupe OH, oxo (=O), SH, NO2, CN, CONH2, COOH, alcoxycarbonyle en C1 à C10, alkylsulfanyle en C1 à C10, alkylsulfinyle en C1 à C10, alkylsulfonyle en C1 à C10, alkyle en C1 à C10, alcoxyle en C1 à C10 et cycloalkyle en C3 à C7.
  2. Composé selon la revendication 1 dans lequel :
    A est sélectionné parmi O, S, N(R3) ou C(R3)R4,
    R1 est sélectionné dans le groupe constitué du groupe aryle, aryl(alkyle en C1 à C6) et hétéroaryle, éventuellement substitué par un ou plusieurs substituants sélectionnés parmi les atomes d'halogène, le groupe alkyle en C1 à C10, alcoxyle en C1 à C10, aryloxy et hétéroaryle.
  3. Composé selon la revendication 1 ou 2 dans lequel :
    A est C(R3)R4,
    m et n ont tous deux la valeur de 2,
    R1 est sélectionné dans le groupe constitué du groupe aryle et hétéroaryle, éventuellement substitué par un ou plusieurs substituants sélectionnés parmi les atomes d'halogène, le groupe alkyle en C1 à C10, alcoxyle en C1 à C10, aryloxy et hétéroaryle ;
    R2 est un groupe de formule (Y)

            ---(CH2)p---P---(CH2)q---W     (Y)

    dans laquelle
    p à la valeur de 0, 1 et 3,
    P est le groupe CO,
    q à la valeur de 0,
    W est sélectionné dans le groupe constitué du groupe alkyle en C1 à C10, aryle, hétéroaryle, éventuellement substitué par un ou plusieurs substituants sélectionnés dans le groupe constitué des atomes d'halogène, du groupe alkyle en C1 à C10, alcoxyle en C1 à C10, OH et alcanoyle en C1 à C10.
  4. Composé selon l'une quelconque des revendications 1 à 3 dans lequel :
    W est sélectionné dans le groupe constitué du groupe phényle, benzothioxol, thiophényle et thiazolyle, éventuellement substitué par un ou plusieurs atomes d'halogène, groupe OH, méthyle et acétyle.
  5. Composé selon l'une quelconque des revendications 1 à 4 où :
    X- est sélectionné dans le groupe constitué des anions comprenant le chlorure, bromure, iodure, trifluoroacétate, formate, sulfate, phosphate, méthanesulfonate, nitrate, maléate, acétate, citrate, fumarate, tartrate, oxalate, succinate, benzoate et p-toluènesulfonate.
  6. Composé de formule (II) :
    Figure imgb0054
     dans laquelle :
    A peut être une simple liaison, une double liaison, l'atome O, S, le groupe SO, SO2, NR3, C(R3)R4, CO, C(O)N(R3), N(R3)C(O)O, SO2N(R3), OC(O)N(R3), C(R3)=C(R4) et C(R3)-(CH2)-C(R4)
    m est un nombre entier d'une valeur de 1 à 4 ;
    n à la valeur de 0 ou est un nombre entier d'une valeur de 1 à 4. ;
    R1 est sélectionné dans le groupe constitué du groupe alkyle en C1 à C10, aryle, cycloalkyle en C3 à C8, hétéroaryle, aryl(alkyle en C1 à C6) et hétéroaryl(alkyle en C1 à C6), éventuellement substitué par un ou plusieurs substituants sélectionnés dans le groupe constitué des atomes d'halogène, du groupe OH, oxo (=O), SH, NO2, CN, CON(R3)2, COOH, CO2R3, CF3, alcoxycarbonyle en C1 à C10, alkylsulfinyle en C1 à C10, alkylsulfonyle en C1 à C10, alkyle en C1 à C10, alcoxyle en C1 à C10, aryloxy et hétéroaryle ;
    R3 et R4 sont indépendamment sélectionnés dans le groupe constitué de l'atome H, des atomes d'halogène, du groupe CONH2, alkyle en C1 à C10, alcynyle en C2 à C6, alcényle en C2 à C6, alcanoyle en C1 à C10, cycloalkyle en C3 à C8, hétéroaryle, et aryle éventuellement substitué par un ou plusieurs substituants sélectionnés dans le groupe constitué des atomes d'halogène, du groupe OH, oxo (=O), SH, NO2, CN, CONH2, COOH, alcoxycarbonyle en C1 à C10, alkylsulfanyle en C1 à C10, alkylsulfinyle en C1 à C10, alkylsulfonyle en C1 à C10, alkyle en C1 à C10, alcoxyle en C1 à C10 et cycloalkyle en C3 à C7 et son sel pharmaceutiquement acceptable.
  7. Procédé de préparation d'un composé selon la revendication 1 par :
    (a) couplage d'un composé de formule (IX), dans laquelle K peut être un groupe alcoxy, un groupe hydroxyle ou un atome d'halogène tel que le chlore et A, R1 sont tels que définis selon la revendication 1, avec un composé de formule (X), dans laquelle J est H (l'hydrogène), Na (le sodium), Li (le lithium) ou K (le potassium), pour fournir un composé de formule (II),
    Figure imgb0055
    (b) alkylation d'un composé de formule (II) par des agents d'alkylation de la formule générale (XI)

            X-R2     (XI)

    dans laquelle R2 est tel que défini selon la revendication 1 et X est un groupe partant approprié sélectionné dans le groupe constitué des atomes d'halogène et de l'ester sulfonate comprenant le tosylate, les triflates ou le mésylate pour fournir des composés de formule générale (I).
  8. Composé de formule (II), selon la revendication 6 utile comme intermédiaire pour la préparation d'un composé de formule (I).
  9. Composé de formule (I), selon l'une quelconque des revendications 1 à 5 pour l'utilisation comme médicament.
  10. Composé de formule (II), selon la revendication 6 pour l'utilisation comme médicament.
  11. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 6, en mélange par admixtion avec un ou plusieurs supports ou excipients pharmaceutiquement acceptables.
  12. Composition pharmaceutique selon la revendication 11 sous une forme sélectionnée dans le groupe constitué d'une poudre pour inhalation, d'un dispositif d'inhalation doseur sous pression à agent propulseur et d'une formulation nébulisée exempte d'agent propulseur.
  13. Combinaison d'un composé selon l'une quelconque des revendications 1 à 6 avec un ou plusieurs ingrédients pharmaceutiquement actifs actuellement utilisés dans le traitement des troubles respiratoires, inflammatoires obstructifs.
  14. Combinaison selon la revendication 13 dans laquelle le un ou plusieurs ingrédients pharmaceutiquement actifs actuellement utilisés dans le traitement des troubles respiratoires, inflammatoires obstructifs est sélectionné dans la classe des agonistes bêta2, des corticostéroïdes et des agents anticholinergiques ou antimuscariniques.
  15. Composé selon l'une quelconque des revendications 1 à 6, éventuellement en combinaison avec un ou plusieurs ingrédients pharmaceutiquement actifs pour l'utilisation dans la prévention et/ou le traitement d'une maladie respiratoire telle que celle provenant d'états modérés à aigus sévères d'asthme et de MPOC.
EP12818780.4A 2011-12-30 2012-12-19 Esters de quinuclidine et d'acide 1-azahétérocyclylacétique utilisés comme agents antimuscariniques, procédé pour leur préparation et compositions médicinales correspondantes Active EP2797910B1 (fr)

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CN1832948B (zh) 2001-12-20 2011-06-15 基耶西药品股份公司 1-烷基-1-氮*双环[2.2.2]辛烷氨基甲酸酯衍生物及其用作蕈毒碱受体拮抗剂的用途
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WO2009153536A1 (fr) 2008-06-17 2009-12-23 Argenta Discovery Limited Dérivés de 1-aza-bicyclo [2.2.2] octane utiles en tant qu’antagonistes des récepteurs muscariniques
EP2154136A1 (fr) 2008-08-08 2010-02-17 CHIESI FARMACEUTICI S.p.A. Dérivés de carbone de quinuclidine et ses compositions médicales
EP2206712A1 (fr) 2008-12-23 2010-07-14 CHIESI FARMACEUTICI S.p.A. Dérivés d'amino-ester d'alcaloïde et sa composition médicale
WO2011160920A1 (fr) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Formulation de poudre sèche comprenant un médicament antimuscarinique
BR112012031967A2 (pt) 2010-06-22 2019-09-24 Chiesi Farm Spa composto, uso de um composto, combinação de um composto e composição farmacêutica
BR112012032332A2 (pt) * 2010-06-22 2016-11-08 Chiesi Farma Spa composto, uso de um composto, composição farmacêutica, combinação de um composto e dispositivo
CA2803416A1 (fr) 2010-06-22 2011-12-29 Chiesi Farmaceutici S.P.A. Derives aminoester d'alcaloides et composition medicinale les comprenant
KR20130140672A (ko) 2010-10-20 2013-12-24 키에시 파르마슈티시 엣스. 피. 에이. 기침 치료용 카보네이트 유도체
WO2012069275A1 (fr) 2010-11-26 2012-05-31 Chiesi Farmaceutici S.P.A. Dérivés de glycine et leur utilisation en tant qu'antagonistes des récepteurs muscariniques
CN103502213B (zh) 2011-04-29 2016-09-28 奇斯药制品公司 生物碱酯及其氨基甲酸酯衍生物和医学组合物

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CN104011043B (zh) 2016-11-16
EP2797910A1 (fr) 2014-11-05
AR089505A1 (es) 2014-08-27
BR112014013179A2 (pt) 2017-06-13
KR20140105746A (ko) 2014-09-02
US8748613B2 (en) 2014-06-10
WO2013098145A1 (fr) 2013-07-04
RU2014126064A (ru) 2016-02-20
CN104011043A (zh) 2014-08-27
HK1200165A1 (en) 2015-07-31
RU2628082C2 (ru) 2017-08-14
CA2862008A1 (fr) 2013-07-04

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